β-lactams increase the antibacterial activity of daptomycin against clinical methicillin-resistant Staphylococcus aureus strains and prevent selection of daptomycin-resistant derivatives

Shrenik Mehta, Christopher Singh, Konrad B. Plata, Palas K. Chanda, Arundhati Paul, Sarah Riosa, Roberto R. Rosato, Adriana E. Rosato

Research output: Contribution to journalArticle

103 Scopus citations

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) has emerged to be one of the most important pathogens both in health care and in community-onset infections. Daptomycin (DAP) is a cyclic anionic lipopeptide recommended for treatment of skin infections, bacteremia, and right-sided endocarditis caused by MRSA. Resistance to DAP (DAPr) has been reported in MRSA and is mostly accompanied by a parallel decrease in oxacillin resistance, a process known as the "seesaw effect." Our study provides evidence that the seesaw effect applies to other β-lactams and carbapenems of clinical use, including nafcillin (NAF), cefotaxime (CTX), amoxicillin-clavulanic (AMC), and imipenem (IMP), in heterogeneous DAPr MRSA strains but not in MRSA strains expressing homogeneous β-lactam resistance. The antibacterial efficacy of DAP in combination with β-lactams was evaluated in isogenic DAP-susceptible (DAPs)/Dapr MRSA strains originally obtained from patients that failed DAP monotherapy. Both in vitro (MIC, synergy-kill curve) and in vivo (wax worm model) approaches were used. In these models, DAP and a β-lactam proved to be highly synergistic against both heterogeneous and homogeneous clinical DAPr MRSA strains. Mechanistically, β-lactams induced a reduction in the cell net positive surface charge, reverting the increased repulsion provoked by DAP alone, an effect that may favor the binding of DAP to the cell surface. The ease of in vitro mutant selection was observed when DAPsMRSA strains were exposed to DAP. Importantly, the combination of DAP and a β-lactam prevented the selection of DAPr variants. In summary, our data show that the DAP-β-lactam combination may significantly enhance both the in vitro and in vivo efficacy of anti-MRSA therapeutic options against DAP r MRSA infections and represent an option in preventing DAP r selection in persistent or refractory MRSA infections.

Original languageEnglish (US)
Pages (from-to)6192-6200
Number of pages9
JournalAntimicrobial Agents and Chemotherapy
Volume56
Issue number12
DOIs
StatePublished - Dec 2012

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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